Multiple sclerosis (MS) is an inflammatory disease of the brain and spinal cord characterized by recurrent foci of inflammation that lead to destruction of the myelin sheath. In many areas, nerve fibers are also damaged. Inflammatory activity in MS patients tends to be highest in the initial phase of disease.
Emerging data demonstrate that irreversible axonal loss occurs early in the course of MS. Transected axons fail to regenerate in the central nervous system (CNS); and therefore, early treatment aimed at suppressing MS lesion formation is of importance. As early as disease onset, axons are transected in lesions with active inflammation (Trapp et al. (1998) N Engl J Med 338: 278-285; Bjartmar et al. (2001) Curr Opin Neurol 14: 271-278; Ferguson et al. (1997) Brain 120: 393-399). The degree of demyelination is related to the degree of inflammation and the exposure of demyelinated axons to the inflammatory environment, as well as non-inflammatory mediators (Trapp et al. (1998) N Engl J Med 338: 278-285; Kornek et al. (2000) Am J Pathol 157: 267-276; Bitsch et al. (2000) Brain 123: 1174-1183). There is also destruction of oligodendrocytes and impaired remyelination in demyelinating lesions (Peterson et al. (2002) J Neuropathol Exp Neurol 61: 539-546; Chang et al. (2002) N Engl J Med 346: 165-173). A loss of oligodendrocytes leads to a reduction in the capacity to re-myelinate and may also result in the loss of trophic factors that support neurons and axons (Bjartmar et al. (1999) J Neurocytol 28: 383-395).
Optic neuritis, e.g., acute optic neuritis (AON), is characterized by inflammatory white matter lesions in the optic nerve. It is often associated with MS and is one the most common initial manifestations of the disease. AON causes structural and functional optic nerve damage (e.g., neuroaxonal injury and demyelination) that can result in permanent visual impairment for some patients (Cole, S. R. et al. Invest Ophtalmol Vis Sci (2000) 41(5):1017-1021; Mi, S. et al. CNS Drugs 2013: 27(7):493-503; Mangione C M et al. Arch Ophthalmol. (1988) 116(11):1496-1504). The current treatment for acute optic neuritis is high dose steroids which provides mostly symptomatic relief and fails to enhance CNS remyelination or provide neuroaxonal protection (Beck R W et al. N Engl J Med 1992 326:581-8).
Currently approved therapies for MS are primarily immunomodulatory, and typically do not have direct effects on CNS repair. Although some degree of axonal remyelination by oligodendrocytes takes place early during the course of MS, typically, in younger patients, the ability to repair the CNS eventually fails, leading to irreversible tissue injury and an increase in disease-related disabilities. Thus, there is a need for additional therapies that enhance remyelination and neuroaxonal protection in CNS demyelinating diseases, such as MS and optic neuritis.